Ischemia/reperfusion injury (IRI) is a common clinical pathophysiological process characterized by ischemia and hypoxia. Hypoxia-inducible factors (HIFs) are a group of transcription factors vital to cell responding and adapting to hypoxia environment. Hypoxia can activate HIF, thus enhancing the tolerance of cells to hypoxia. The role of HIF in IRI has become a research focus of many scientists. Elucidating the related mechanism can not only help to reduce IRI, but also lay a basis for further studying the role of HIF in other pathophysiological processes. In this paper, we reviewed the structure, function of HIF and the specific role and related mechanisms of HIF in IRI.